Mitochondria, central to metabolic processes, is involved energy production, programmed cell death, and reactive oxygen species (ROS) generation, and is heavily implicated in various stages of major diseases including cancer, diabetes, neurodegenerative diseases, and aging; yet its role in the pathogenesis still remains largely unclear. Traditionally, mitochondria have been considered as “end-function” organelles, receiving and processing vast amounts of cellular signals to regulate energy production and cell death. However, retrograde signaling, whereby the mitochondria communicate back to the cell, is a poorly understood biological process.
Calcium, cytochrome C, and ROS have been considered a retrograde mitochondrial molecule. Notably, Durieux et al. proposed that signals originating from mitochondria can regulate the lifespan of C. elegans in a cell non-autonomous manner, but the nature of such signals has not been identified in worms (Durieux et al., Cell 144, 79 (Jan. 7, 2011). The identity of such mitochondria-derived signals may have been discovered in 2001, when a 24 amino acid peptide, now known as humanin (HN), was cloned from a cDNA library constructed from the surviving fraction of an Alzheimer patient's brain and was mapped to the mitochondrial 16S rRNA locus (Hashimoto et al., Proc Natl Acad Sci USA 98, 6336 (May 22, 2001). Since then, HN has been shown to be a cytoprotective and anti-apoptotic factor, partially due to its role as a Bax antagonist that prevents apoptosis in various cancer cells (Guo et al., Nature 423, 456 (May 22, 2003) as an IGFBP-3 partner that antagonizes the apoptotic actions of IGFBP-3 on cancer cells (Ikonen et al., Proc Natl Acad Sci USA 100, 13042 (Oct. 28, 2003). More recent work indicates that HN is a wide spectrum survival factor (Nishimoto et al., Trends Mol Med 10, 102 (March, 2004)), however, its exact mechanism of action remains unclear.
Mitochondria-derived humanin shares 92-95% identity with several nuclear-encoded cDNAs, which represent domains within larger hypothetical genes, whose expression has not been validated (Tajima et al., Neurosci Lett 324, 227 (May 24, 2002)). HN transcripts of mitochondrial origin are present in kidney, testis, brain, and the gastrointestinal tract. Of note is that humanin is highly conserved among species (between 90-100% homology), including lower organisms. The peptide has been demonstrated in brain and testis and we have shown that it is present in 1-10 ng/ml concentrations in plasma, CSF and seminal fluid. Novel mutants and analogs of HN with more potent actions have been described, including HNG (S14G), HNG-F6A (non-IGFBP-3 binding, which we have recently protected as a possible type-2 diabetes treatment under a joint AECOM/UCLA patent that has been submitted) and colivelin (hybrid peptide containing partial sequences of HN and ADNF9). Humanin and its analogues and derivatives are showing therapeutic potential for an array of diseases including Alzheimer's disease, diabetes and kidney failure.
This report is the first description of a novel open-reading frame (ORF) in the 12S rRNA. The name of this novel ORF in the 12S rRNA is Mitochondrial ORF in the Twelve S rRNA 3 (MOTS3). Similar to HN (Y. Hashimoto et al., Proc Natl Acad Sci USA 98, 6336 (May 22, 2001)), the MOTS3 transcripts are polyadenylated and suggest a gene within-a-gene structure that is well conserved throughout species.
MOTS3 is detected in the liver, heart, testis at the same molecular weight, but found with a slightly higher molecular weight in the brain of mice and rats. Its main biological function is metabolic regulation with strong influence on mitochondrial respiration and glucose utilization in both cell culture and mice. MOTS3 has also been tested in various ways in vitro and in vivo to affect mitochondrial respiration, glucose utilization, insulin regulation and cellular proliferation/survival.
Furthermore, MOTS3 is a non-toxic natural peptide derived from the mitochondria that has a general metabolic regulatory role. It is the first of its kind that provides strong body weight and blood glucose regulation as well as activation of AMPK which is a major drug target for diabetes and cancer via the mTOR pathway. It is from an entirely novel category of drugs, i.e. mtDNA-derived signaling peptides that have only recently been described. Accordingly, MOTS3 and pharmaceutical formulations thereof can be used to treat various age-related disease with much metabolic implications such as cancer, diabetes, obesity, and neurodegenerative diseases are not sufficient to cure the disease.
Accordingly, this invention discloses the novel MOTS3 ORFs and methods of use thereof to treat disease.